In 1980 we described a new form of viral hepatitis caused by a previously unrecognized hepatitis virus with epidemiologic characteristics of HAV (i.e., the virus is fecal-orally transmitted, produces water-borne epidemics and is probably responsible for a significant proportion of endemic hepatitis) but not related to HAV. The disease has been called epidemic or enterically transmitted non-A, non-B hepatitis or hepatitis E. Such hepatitis is both epidemic and endemic throughout the Indian subcontinent, central Asia, parts of the Middle East and northern Africa, with probable extension to West Africa. Epidemics of the disease have also occurred in Mexico. The putative etiologic agent, a 27-30nm nonenveloped virus, was identified in a volunteer study in 1983 and similar virus-like particles have been detected in feces of cases in a number of other outbreaks. The small quantity of such virus-like particles available for study has limited progress but it is now possible to biologically amplify the virus by collecting bile from experimentally infected cynomologous monkeys. These monkeys as well as chimpanzees develop an elevation of liver enzymes 28 days past inoculation. Efforts to amplify HEV molecularly by reverse transcription and PCR have been successful and partial sequences of two HEV strains have been obtained. In 1989 a possible paramyxovirus etiology for neonatal (giant cell) hepatitis was proposed, based on electron micrographic changes seen in the livers of patients with this disease. Collaborative studies, including attempts to transmit the disease to primates, have been initiated. The objectives of this project are to identify and characterize new etiologic agents of hepatitis and to develop useful assays for diagnosis of infection and seroepidemiologic studies. A longer term objective is the development of passive and active immunoprophylaxis for these important human pathogens.